17-75501124-T-C

Variant names:

• chr17-75501124-T-C
• NM_020753.5:c.3565A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020753.5(CASKIN2):​c.3565A>G​(p.Met1189Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CASKIN2 NM_020753.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

CASKIN2 (HGNC:18200): (CASK interacting protein 2) This gene encodes a large protein that contains six ankyrin repeats, as well as a Src homology 3 (SH3) domain and two sterile alpha motif (SAM) domains, which may be involved in protein-protein interactions. The C-terminal portion of this protein is proline-rich and contains a conserved region. A related protein interacts with calcium/calmodulin-dependent serine protein kinase (CASK). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASKIN2	NM_020753.5	c.3565A>G	p.Met1189Val	missense_variant	Exon 20 of 20	ENST00000321617.8	NP_065804.2
CASKIN2	NM_001142643.3	c.3319A>G	p.Met1107Val	missense_variant	Exon 19 of 19		NP_001136115.1
CASKIN2	XM_047436459.1	c.3565A>G	p.Met1189Val	missense_variant	Exon 20 of 20		XP_047292415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASKIN2	ENST00000321617.8	c.3565A>G	p.Met1189Val	missense_variant	Exon 20 of 20	1	NM_020753.5	ENSP00000325355.3
CASKIN2	ENST00000433559.6	c.3319A>G	p.Met1107Val	missense_variant	Exon 19 of 19	2		ENSP00000406963.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440614 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3565A>G (p.M1189V) alteration is located in exon 20 (coding exon 19) of the CASKIN2 gene. This alteration results from a A to G substitution at nucleotide position 3565, causing the methionine (M) at amino acid position 1189 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.98	D;.
Vest4		0.61
MutPred		0.59		Loss of disorder (P = 0.0155);.;
MVP		0.86
MPC		0.34
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.69
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-73497205;